Non-steroidal anti-inflammatory compounds to treat inflammation

ABSTRACT

A non-steroidal anti-inflammatory composition comprising an active anti-inflammatory agent having the formula: ##STR1## wherein R 1 , R 2  and R 3  is hydrogen, hydroxy, phenyl, methoxy, carboxylic acid, sulfhydryl or hydroxamic acid. 
     The active agent is formulated with a pharmaceutically acceptable carrier for use in the treatment of pain, inflammation and other related symptoms on mammals. p-Hydroxydiphenyl, p-methoxyphenol, thiosalicylic acid, benzyl alcohol and salicylhydroxamic acid are preferred.

The present invention relates to non-steroidal anti-inflammatorycompounds useful as active agents in the treatment of pain,inflammation, swelling and other related symptoms of mammals. Thisinvention also relates to pharmaceutically acceptable compositionscontaining these actives as well as a method of treatment.

Non-steroidal anti-infammatory compounds are well-known in the art.Examples of such compounds are aspirin, indomethacin, andphenylbutazone, to name a few. All of these have claims associated withthem for the treatment of pain and inflammation in mammals. Thesecompounds are known to cause side-effects, gastroenteric disorders andheadaches.

U.S. Pat. No. 4,145,444 to Hamazaki et al., discloses variousnon-carboxylic benzoyl derivatives as anti-inflammatory agents. Inparticular, those compounds disclosed have the formula ##STR2## whereinR₁ represents hydrogen, halogen, hydroxy, C₁₋₈ alkyl or C₁₋₈ alkoxy; R₂represents hydrogen, halogen, hydroxy, vinyl, C₁₋₈ alkyl or C₁₋₈ alkoxy;A represents carbonyl, methylene or a single bond; and n is an integerof 1 to 4. It is preferred that R₂ be n-butyl substituted in the orthoor para position, and R₁ be hydrogen or halogen, e.g., compounds havingthe chemical name 4-n-butylbenzophenone or4-n-butyl-2'-fluorobenzophenone.

U.S. Pat. No. 4,244,970 to Dewhirst discloses a method of treatinginflammation and inhibiting prostaglandin synthesis by administering aneffective amount of 2-hydroxybenzophenone and substitutes thereof. Thispatent discloses only those compounds having one hydroxy group locatedat the ortho position on at least one of the benzene rings.

The association between the production of prostaglandins in mammals andinflammation and pain is well documented. See Greaves and Sondergaard,Journal of Investigative Dermatology 72:59-63, 1979, where it was firstdemonstrated that prostaglandin activity was present in tissue fluidtaken from inflamed human skin. Other investigators have subsequentlyreported that PGE₂ (prostaglandin E₂) concentrations in skin increaseafter exposure to ultraviolet (UVB) light and mediate a significantdegree of redness and inflammation, particularly in the first 24 hourssubsequent to exposure.

Without wishing to be bound by any one theory, it is believed that theinventive compounds and compositions based thereon, particularly thosecontaining p-hydroxydiphenyl, benzylalcohol, thiosalicylic acid,p-methoxyphenol and salicylhydroxamic acid are effective prostaglandininhibitors. It is theorized that the effective inhibition ofprostaglandin synthesis is the mechanism by which the novel compoundsreduce and control pain and inflammation in mammals.

The literature has clearly shown that non-steroidal anti-inflammatoryagents will reduce ultraviolet induced erythema by inhibiting theproduction of prostaglandin E₂ within the first 24 hour periodsubsequent to UVB exposure. See "Prostaglandins in the Skin," by Neal S.Penneys, published by Upjohn Co., 1980.

It is apparent that there is a need for effective, novel non-steroidalanti-inflammatory compounds which can be formulated into compositionsusing pharmaceutically acceptable carriers for topical, rectal, oral,perlingual or parenteral administration. The novel, instant compoundsfulfill this need.

The instant invention relates particularly to the use of the compoundhaving the structural formula below: ##STR3## wherein R₁, R₂ and R₃represent hydrogen, hydroxy, phenyl, methoxy, carboxylic acid,sulfhydryl or hydroxamic acid and R₁ additionally representshydroxymethyl.

When R₁ is a phenyl group, R₂ is a hydrogen and R₃ is a hydroxyl group,the compound is commonly known as p-hydroxydiphenyl. When R₁ is ahydroxymethyl group, and R₂ and R₃ are both hydrogens, the compound iscommonly known as benzyl alcohol. When R₁ is a carboxylic acid group, R₂is a sulfhydryl group, and R₃ is a hydrogen, the compound is commonlyknown as thiosalicylic acid. When R₁ is a methoxy group, R₂ is ahydrogen, and R₃ is a hydroxyl group, the compound is commonly known asp-methoxyphenol. When R₁ is a hydroxamic acid group, R₂ is a hydroxylgroup, and R₃ is a hydrogen, the compound is commonly known assalicylhydroxamic acid. These compounds, alone or in combination, areuseful in relieving pain and inflammation.

While these compounds were previously known, heretofore they have notbeen disclosed as anti-inflammatory or pain relieving compounds.p-Hydroxydiphenyl is often used as an intermediate in the manufacturingof resins (page 7111, 9th edition, Merck Index). Benzyl alcohol is oftenused as a bacteriostat and as a perfuming agent (p 1138, 9th edition,Merck Index). Thiosalicylic acid is often used in the manufacturing ofthioindigo dyes (page 9099, 9th edition, Merck Index). p-Methoxypehenolis often used as a depigmentation agent. Salicylhydroxamic acid is oftenused as a topical anti-fungal agent (page 8092, 9th edition, MerckIndex).

The inventive compounds, when administered in therapeutically effectiveamounts, either alone or in a pharmaceutically acceptable carrier, areeffective as a remedy for pain, inflammation and other related symptomsin mammals.

The instant compounds are generally used in a therapeutically effectiveamount, but when contained in a pharmaceutically acceptable carrier orcomposition, are generally present in amounts of about 0.05% to about35% by weight of the composition; preferably in amounts of about 0.1% toabout 15% and most preferably about 0.1% to about 1% by weight of thecomposition.

The inventive compounds are preferably used in a composition which canbe easily and conveniently administered to a mammal experiencing painand inflammation. As mentioned above, dosage forms may be varied andinclude topical creams, pastes, ointments, gels, lotions and the like,for direct application to the inflammed area. Oral dosage forms include,but are not limited to capsules, tablets, solutions, syrups, powders andthe like. Rectal, perlingual and parenteral dosage forms are alsocontemplated.

The instant compounds and their compositions are intended for use in thetreatment of a variety of inflammatory problems and diseases includingsystemic diseases such as arthritis and the like.

The preferred dosage form is a topical lotion comprising the inventivecompounds or mixtures thereof in a pharmaceutically acceptable carrier.Illustrations of useful carriers include ethanol and other lower alkylalcohols, polyalcohols, mineral oils, vegetable oils, petrolatum,glycerine, nonionic surfactants, water and the like, as well as mixturesof these. Compositions comprising from about 0.05% to about 20% byweight of the inventive compounds in the above carriers have been foundparticularly effective in the treatment of inflammation of the skin,commonly known in the art as erythema.

The active anti-inflammatory compounds of the instant invention can beapplied together with other anti-inflammatory agents, analgesics,thrombus dissolving agents, thrombus inhibiting agents, antibiotics andthe like.

In the case where the active compounds are incorporated in apharmaceutical composition, other common materials such as lubricants,humectants, surfactants, waxes, emulsifiers, thickeners, emollients,preservatives, demulcents, perfumes, coloring additives and the like maybe added. These, of course, are not critical to the invention and theiramounts can be varied and balanced to meet the desired properties of theoverall composition, which is discoverable by routine experimentation byone skilled in the art.

The instant compositions may include materials that serve as occlusivesin that they hold moisture against the surface of the skin. Suitableocclusive compounds include cetyl alcohol, cetyl palmitate, petrolatum,mineral oil and the like. These materials are generally present intopical compositions, for example, in amounts of about 1% to about 25%by weight of the composition and preferably in amounts of about 2% toabout 10%.

A variety of materials may be utilized as emulsifiers, including highmolecular weight polyethylene glycols, fatty alcohols such as stearylalcohol and myristyl alcohol and the like. These materials are generallypresent in amounts of about 0.1% to about 15% by weight of thecomposition and preferably in amounts of about 1% to about 10%.

Suitable emollients for use in the instant compositions containing thenovel anti-inflammatory compounds include fatty acid esters such ascetyl palmitate, diisopropyl adipate, isopropyl isostearate, isostearylisostearate and mixtures thereof, to name a few. Generally they arepresent in topical compositions in amounts of about 0.1% to about 20% byweight of the composition and preferably in amounts of about 1% to about10%.

Suitable humectants may be any of those well known in the art. Examplesof useful humectants include glycerin, propylene glycol, polyethyleneglycol, polyhydric alcohols and mixtures thereof, to name a few.Preferably, glycerin is used. These materials may be incorporated in theinventive anti-inflammatory compositions in amounts of about 0.1% toabout 30% by weight of the composition and preferably in amounts ofabout 3% to about 20%.

Numerous surfactants, and preferably non-ionic surfactants, may be addedfor their intended purpose. Among those preferred are polyalkanolaminessuch as triethanolamine, polyethylene glycol stearate, polyethyleneglycol laurate, polyoxyethylene and polyoxypropylene compounds, e.g. asderivatives of sorbitan and fatty alcohol esters, fatty acid esters ofpolyhydric alcohols and amine oxides; anionic surfactants, such as alkylcarboxylates, acyl lactylates, sulfuric acid esters (e.g. sodium laurylsulfate), 5 ester-linked sulfonates, and phosphated ethoxylatedalcohols; cationic surfactants, such as monoalkyl and dialkyl quaternaryammonium salts, amidoamides and aminimides. These various surfactants,when compatable, can be added as mixtures to the instant compositionsand are generally present in amounts of about 0.1% to about 15% byweight of the composition.

Lubricating agents may be used when desired in the instant compositions.They include silicone oils or fluids such as substituted andunsubstituted polysiloxanes, e.g. dimethyl polysiloxane, also known asdimethicone, is particularly useful when the composition is to be usedas a topical preparation. The lubricating agents, when incorporated in atopical composition, are generally present in amounts of about 0.1% toabout 30% by weight of the composition and preferably in amounts ofabout 1% to about 10%. Other lubricating agents well known to thetableting and capsule art may be used when the dosage form is a tablet,pill or capsule. These lubricating agents are primarily to aid information of tablets.

Preservatives such as alkyl and aryl parabens and substituted phenolsare also useful additives. Examples of the preferred parabens are themethyl, propyl and butyl parabens useful in ranges of 0.1 to about0.25%. In a preferred embodiment, a combination of methyl, propyl andbutyl paraben may be used in the respective ranges of about 0.1% toabout 0.25%, 0.02% to about 0.2% and 0 to about 0.05%. Examples of theuseful substituted phenols include chloro-substituted phenoxy phenols,such as 5-chloro-2-(2,4-dichlorophenoxy)phenol, hexachlorophene,triclosan and dichlorophene, among others.

Other useful preservatives include mercury derivatives, such asphenylmercuric acetate; quarternaries, such as benzethonium chloridebenzalkonium chlorides and cetyl trimethyl ammonium bromide; acids, suchas sorbic acid; and a variety of other preservatives such as Kathon CG,a trademark of Rohm & Haas Co. which comprises a mixture of5-chloro-2-methyl-4-isothiazolin-3-one and2-methyl-4-isothiazolin-3-one.

Other conventional additives may be utilized, such as fragrance oils,thickeners, emulsifiers and other additives. For example, in the case ofa topical lotion, thickeners for viscosity adjustment would includexanthan gum, sodium stearyl sulfate, and materials of that type.

The foregoing recitation of materials is presented for purposes ofillustration and not limitation, it being understood that a variety ofequivalent materials would all function in the capacities set forthabove.

The instant invention also includes a method of treatment forinflammation, pain and related symptoms whereby a mammal is administereda therapeutically effective amount of the compound having the structuralformula: ##STR4## wherein R₁, R₂ and R₃ represent hydrogen, hydroxy,phenyl, methoxy, carboxylic acid, sulfhydryl or hydroxamic acid and R₁additionally represents hydroxymethyl.

The invention will be further appreciated by the following example whichis intended to illustrate an embodiment of the instant invention. Allpercentages throughout the specification are by weight of the totalcomposition unless otherwise indicated.

EXAMPLE

This example is designed after the guinea pig model of Snyder, Journalof Investigative Dermatology, 64:322-25, 1975, and demonstrates thatskin inflamed by ultraviolet light (U.V.B.) can be effectivelytherapeutically treated using a compound of the instant invention.Additionally, this example demonstrates that the instant compounds whenapplied topically in a dermatological preparation are effective ininhibiting the production of prostaglandins which are believed to beresponsible for the inflammation.

The dorsal surface of a male albino guinea pig was shaved with astandard animal clipper (#40 head), depilated with a commerciallyavailable thioglycolate based depilatory product, rinsed with tap waterand dried. The animal was immobilized in a standard head stock andirradiated for 30 minutes. This period of irradiation was found to beequivalent to 3 MED's. An MED (minimum erythemal dose) is the minimalamount of U.V.B. radiation required to produce sunburn 24 hourssubsequent to exposure. The U.V.B. light source was a bank ofWestinghouse FS-40 lamps.

Immediately after irradiation, the animal's exposed dorsal surface wasdelineated with a black marking pen into treatment sites. Some siteswere then treated with ten (10) micro-liters of p-hydroxydiphenyl (3%solution) a preferred embodiment of the instant invention. Additionalcites were treated with ten (10) micro-liters of p-methoxyphenol (3%solution), ten (10) micro-liters of thiosalicylic acid (3% solution),ten (10) micro-liters of benzyl alcohol (3% solution) and ten (10)micro-liters of salicylhydroxamic acid (3% solution), respectively, alsopreferred embodiments of the instant invention. Other areas were treatedwith a substituted 2-hydroxybenzophenone (3% solution) compound as acontrol, this compound being disclosed in 30 U.S. Pat. No. 4,244,970 toDewhirst. The sites were then visually evaluated for lack of erythema(blanching) at 1, 5 and 24 hours post-treatement by a trained,doubleblinded observer. The results, as described below, were based onthe following scale:

0--No Blanching

1--Barely Detectable Blanching

2--Moderate Blanching

3--Severe Blanching

4--Complete Blanching (no erythema)

The results are tabulated below:

    ______________________________________                                                             Blanching Score                                                                            5                                           Agent       Vehicle        1 hr.  hrs. 24 hrs.                                ______________________________________                                        p-hydroxydiphenyl                                                                         90% DMSO*      3      1    0                                      (3%)                                                                          Control (3%)                                                                              90% DMSO       2      2    0                                      p-methoxyphenol                                                                           PG:E + OH:DMA**                                                                               1+     0+  0                                      (3%)                                                                          Control (3%)                                                                              PG:E + OH:DMA   1+     1+  0                                      thiosalicylic                                                                             PG:E + OH:DMA   1+    1    0                                      acid (3%)                                                                     Control (3%)                                                                              PG:E + OH:DMA  2      2    0                                      benzyl alcohol                                                                            PG:E + OH:DMA  1      1    0                                      (3%)                                                                          Control (3%)                                                                              PG:E + OH:DMA   1+     1+  0                                      salicylhydrox-                                                                            PG:E + OH:DMA  1      0    0                                      amic acid (3%)                                                                Control (3%)***                                                                           PG:E + OH:DMA  2      1    0                                      ______________________________________                                         *Dimethylsulfoxide, used in a ratio of 9:1, DMSO to water.                    **Propylene glycol:ethanol:n,N-- dimethylacetamide in the ratio of 10:19:     ***Percents on a weight/weight basis of total product (vehicle and agent)                                                                              

These results indicate that post-irradiation application of a compoundof the instant invention inhibits prostaglandin production as indicatedby the reduction of inflammation evidenced by blanching.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of theclaims.

What is claimed is:
 1. A method for the treatment of inflammation inmammals comprising adminstering a therapeutically effective amount ofthe compound having the formula: ##STR5## wherein R₁ is methoxy,hydroxymethyl, carboxylic acid, phenyl, hydroxy or hydroxamic acid,R₂ ishydrogen, hydroxy or sulfhydryl, and R₃ is hydrogen or hydroxy.
 2. Themethod of claim 1 further comprising applying the compound in a topicalpreparation to the area of pain or inflammation.
 3. The method of claim1 further comprising administering the compound orally.
 4. The method ofclaim 1 further comprising applying the compound rectally.
 5. The methodof claim 1 further comprising administering the compound perlingually orparenterally.
 6. The method of claim 2 further comprising applying thecompound topically in a pharmaceutically acceptable carrier.
 7. Themethod of claim 6 wherein R₁ is phenyl, R₂ is hydrogen and R₃ ishydroxy.
 8. The method of claim 6 wherein R₁ is methoxy R₂ and R₃ arehydrogen.
 9. The method of claim 6 wherein R₁ is carboxylic acid, R₂ issulfhydryl and R₃ is hydrogen.
 10. The method of claim 1 wherein R₁ ismethoxy, R₂ is hydrogen and R₃ is hydroxy.
 11. The method of claim 6wherein R₁ is hydroxamic acid, R₂ is hydroxy and R₃ is hydrogen.
 12. Themethod as in any one of claims 7, 8, 9, 10 or 11 wherein thepharmaceutically acceptable carrier is present in amounts up to about99% and the compound is present in amounts of about 0.05% to about 20%,percents based on the weight of the total composition.